Letters in Drug Design & Discovery - Volume 2, Issue 7, 2005

A series of novel bicyclic proline P2 scaffold based tetrapeptide inhibitors were designed and prepared. Given their relatively small size, these compounds exhibited exceptional binding affinities and good cellular potencies for HCV protease. One of the best analogues, tricyclic based P2 scaffold 12, had an affinity for HCV with a Ki of 37 nM and cell activity IC50 of 200 nM.

Ximelagatran is a prodrug that is rapidly converted to melagatran, a direct, competitive and reversible inhibitor of the active site of human α-thrombin. Its effect is independent from diet, plasma antithrombin levels, obesity or ethnicity. It has little effect on bleeding time at doses up to twice those required, and interference with other drugs is avoided by the absence of interaction with cytochrome P450. Ximelagatran has been documented in a large clinical programme with proven efficacy in prevention and treatment of venous thromboembolism, prevention of stroke in patients with atrial fibrillation and prevention of major cardiovascular events following a recent myocardial infarction. Bleeding has not been a problem, but increase in liver enzymes is a cause of concern for long term use until more information is available.

Selective inhibitors of tyrosine kinase 2 (Tyk2) were searched for using database screening, de novo ligand design and computational docking in Tyk2 and seven other protein kinases. None of the structures in the National Cancer Institute database seem to inhibit Tyk2 selectively, but five of the designed structures seem promising.

The p38 mitogen-activated protein kinase (MAPK) plays an essential role in the normal inflammatory response, however chronic activation of p38 can lead to the development of inflammatory diseases. Several small molecule p38 inhibitors have been developed for the treatment of inflammatory diseases. These inhibitors are used extensively for understanding the requirements for p38 activity in many cellular processes. However, the selectivity of these inhibitors against enzymes outside of the MAPK family has not been broadly addressed. To investigate inhibitor selectivity we have screened several widely used, commercially available p38 inhibitors against a multi-enzyme panel and generated their selectivity profiles. We show that these inhibitors can have potent effects on multiple cellular signaling pathways and we discuss the implications of these findings.

A quantitative structure-activity relationship (QSAR) study has been made on some bicyclic heteroaryl hydroxamic acid analogs acting as matrix metalloproteinase (MMP) inhibitors. The inhibition potencies of compounds against a number of MMPs were subjected to QSAR analysis and it was found surprisingly that the most crucial property of the molecules controlling the drug action, the hydrophobicity, to be playing a negative role here in most of the cases vis-a-vis the polarizability of the molecules is shown to be conducive to the potency. Based on this, it is proposed that the active sites in most of the MMPs might be having electronic nature and, only in a few, there may be some hydrophobic sites.

A series of tetrasubstituted pyrrole derivatives, structurally related to tyrosine kinase inhibitors, has been synthesized one-pot by irradiation of a silica gel absorbed mixture of a conjugated alkynoate and a primary amine. The compounds were evaluated for their anticancer activities using the human breast cancer cell lines, T-47D and MCF7.

Luteinizing hormone-releasing hormone (GnRH) antagonists competitively block pituitary GnRH receptors, thus leading to an immediate decrease of the circulating levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) and consequently of sex steroids. They are clinically used when pharmacologically induced hormone suppression is desired, e.g. in sex steroid dependent benign and malignant diseases and for prevention of premature LH surges in assisted reproduction. The article reviews the clinical experience with the well established GnRH antagonists cetrorelix, ganirelix and the approved, but recently withdrawn abarelix. Clinical studies with the new depot formulations of cetrorelix, teverelix, degarelix and D-63153 are summarized.

The synthesis of some steroidal dioximes (22-29) and their in vitro antineoplastic activity are described in this report. The oximino functionality was incorporated at position 3 and 17 of the 16- benzylidene substituted steroidal nucleus to study the importance of dioximino moiety on anticancer activity. The synthesized compounds were screened for their in vitro antitumor activity against the cell panel consisting of three lines (breast, brain and lungs) at NCI, Bethesda, USA. After selective analysis, compounds 23-28 indicated statistically significant antineoplastic activity for further studies.

The patients' psychiatric diagnoses play a large role in the design and outcome of psychopharmacology clinical trials. Among antidepressant trials, magnitude of placebo response, initial severity of depression, dosing regimen, number of treatment arms and duration of trial, choice of rating scales, and sex of the patient may influence antidepressant trial outcome.

Numerous studies have shown that nicotinamide can prevent cell death via both necrosis and apoptosis. DNA fragmentation, NAD, poly(ADP-ribose) polymerase, apoptosis inducing factors, tumor necrosis factors, p53, caspases, inhibitor of apoptosis proteins and other factors are important in the action of nicotinamide. In this review, the regulatory effect of nicotinamide on individual pro- and anti-apoptotic proteins in neuronal cells have been delineated with a view to present a central molecular mechanism by which nicotinamide prevents apoptosis in the brain.

L-dopa is the most effective drug in the symptomatic management of PD and extends the life span of PD patients.The question whether L-dopa is neurotoxic remains however unresolved. In recent years, increased Homocysteine (Hcy) levels have been observed in L-dopa treated Parkinson's disease (PD) patients, resulting from L-dopa O-methylation by the enzyme catechol-O-methyltransferase. This review summarizes current evidences supporting the possible role of Hcy as mediator of L-dopa toxicity mainly on dopaminergic neurons.

A series of eight N'-[(E)-(disubstituted-phenyl)methylidene]isonicotino-hydrazide derivatives were synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis, and the activity expressed as the minimum inhibitory concentration (MIC) in mg/mL. Four compounds 2b-d and 2f exhibited a significant activity (0.6 mg/mL), when compared with first line drugs such as isoniazid (INH) and rifampin (RIP) and could be a good starting point to develop new lead compounds in the fight against multidrug resistant tuberculosis.

Renal elimination of drugs bound to plasma proteins is mediated mainly by tubular secretion. Furosemide, a frequently used diuretic, is tightly bound to plasma proteins and is believed to be secreted. It contains a carboxyl group and a sulfamoyl moiety and may therefore be a substrate for the sodium-dependent dicarboxylate cotransporter from human kidney (hNaDC-3). Furosemide, besides inhibiting [14C]succinate uptake, reduced succinate-associated currents in a dose-dependent manner with an IC50 of 2.2 mM. Furosemide showed sodium-dependent inward currents as evidence for its translocation by hNaDC-3. The concentrations necessary to affect hNaDC-3, however, are far higher than the therapeutically relevant plasma concentrations of furosemide. This implies that dicarboxylate uptake necessary for drug excretion via organic anion/dicarboxylate exchange will not be altered by therapeutical doses of furosemide.